Hidetada Tachibana

Discordant S-T alternans contributes to formation of reentry: a possible mechanism of reperfusion arrhythmia

Although a relationship between S-T alternans and life-threatening arrhythmia has been recognized, the mechanism is poorly understood. We examine the role of S-T alternans in the occurrence of ventricular fibrillation (VF) after reperfusion. The left anterior descending coronary artery was occluded for 20 min and then abruptly reperfused in 12 intravenously anesthetized open-chest dogs. Sixty unipolar epicardial electrograms were recorded during the control state, at the end of occlusion, and after reperfusion. The largest magnitude of S-T alternans among 60 leads was defined as the maximum S-T alternans. Isochronal maps of activation time in paced beat and spontaneous ventricular premature contractions (VPC) were analyzed. After reperfusion, VF ensued in six dogs. The maximum S-T alternans augmented progressively with time after reperfusion until VF occurred. In three dogs with VF, when activation of VPC resulted in conduction block and formed reentry, VF ensued. The conduction block was located between sites of discordant S-T alternans (S-T alternans at adjacent leads was out of phase). These data indicate that discordant S-T alternans relates to VF by facilitating the formation of a reentrant circuit.Although a relationship between S-T alternans and life-threatening arrhythmia has been recognized, the mechanism is poorly understood. We examine the role of S-T alternans in the occurrence of ventricular fibrillation (VF) after reperfusion. The left anterior descending coronary artery was occluded for 20 min and then abruptly reperfused in 12 intravenously anesthetized open-chest dogs. Sixty unipolar epicardial electrograms were recorded during the control state, at the end of occlusion, and after reperfusion. The largest magnitude of S-T alternans among 60 leads was defined as the maximum S-T alternans. Isochronal maps of activation time in paced beat and spontaneous ventricular premature contractions (VPC) were analyzed. After reperfusion, VF ensued in six dogs. The maximum S-T alternans augmented progressively with time after reperfusion until VF occurred. In three dogs with VF, when activation of VPC resulted in conduction block and formed reentry, VF ensued. The conduction block was located between sites of discordant S-T alternans (S-T alternans at adjacent leads was out of phase). These data indicate that discordant S-T alternans relates to VF by facilitating the formation of a reentrant circuit.

Glibenclamide attenuates peaked T wave in early phase of myocardial ischemia

OBJECTIVES ECG peaked T wave appears during the early phase of myocardial ischemia, but the underlying mechanisms remain unknown. The purpose of this study was to elucidate the role of ATP-sensitive K+ channel (KATP) in this ECG change. METHODS In 12 anesthetized, open-chest dogs, the sinus node was crushed and the right atrium was paced at a cycle length of 400 ms. The left anterior descending coronary artery was abruptly occluded for 60 s before (control) and 15 min after an intravenous infusion of vehicle (n = 6) or glibenclamide (1 mg/kg, n = 6), a blocker of KATP. Forty-eight epicardial electrograms were simultaneously recorded from the anterior surface of the left ventricle. The potentials at 40, 80 and 120 ms from the J point were measured, and these points corresponded to the early, middle and late phases of the T wave, respectively. RESULTS During the control occlusion, T wave increased time-dependently and the maximal T-wave change was noted at the end of 60 s of coronary occlusion. The extents of T-wave elevation at the early, mid and late T phases were 5.5 +/- 0.5, 7.3 +/- 0.8 and 11.7 +/- 1.8 mV, respectively, and these T-wave elevations were significantly reduced by 33 +/- 21%, 59 +/- 12% and 63 +/- 13%, respectively, after the pretreatment with glibenclamide but not with its vehicle. The % reductions of mid and late T by glibenclamide were significantly larger than that of early T wave (P < 0.05). CONCLUSIONS An abrupt coronary occlusion accompanied peaked T wave as an early ECG wave change. As the extent of this T-wave elevation was attenuated by glibenclamide, the ischemia-induced alteration of ventricular repolarization can partly (60%) be explained by the modification of KATP activation.

Intracoronary Flecainide Induces ST Alternans and Reentrant Arrhythmia on Intact Canine Heart A Role of 4-Aminopyridine–Sensitive Current

BACKGROUND The electrical alternans shown on an ST segment, ST alternans, is known as one of the most important predictors of ventricular fibrillation (VF). It has also been reported that sodium channel inhibition changes action potential configuration, especially on the repolarization phase. Thus, the sodium channel blocker may produce ST alternans and trigger reentrant arrhythmia. METHODS AND RESULTS A sodium channel blocker (disopyramide, lidocaine, or flecainide) was infused selectively into the left anterior descending coronary artery in anesthetized, open-chest dogs. Sixty unipolar electrograms were simultaneously recorded from the entire cardiac surface of the heart. The amplitude of ST alternans (STa) was determined as the difference in the ST-segment magnitude between 2 consecutive electrograms. We accepted the greatest STa among 60 leads for evaluation. High-dose flecainide (100 microg. kg-1. min-1) increased STa and evoked a spontaneous VF. The STa in high-dose flecainide loading (8.7+/-3.4 mV; mean+/-SEM) was significantly greater than that in disopyramide or lidocaine (0. 9+/-0.4 and 0.8+/-0.2 mV, P<0.05). Treatment of 4-aminopyridine (4-AP) suppressed the increase in STa and the occurrence of VF evoked by flecainide, while E4031 or verapamil did not inhibit those. CONCLUSIONS Flecainide caused the ST alternans that was closely correlated to the occurrence of VF. Because the ST alternans was suppressed by 4-AP treatment, a 4-AP-sensitive current such as Ito or Isus may play an important role on this phenomenon.

Angiotensin-converting enzyme inhibition improves cardiac fatty acid metabolism in patients with congestive heart failure.

Summary This study aimed to examine whether angiotensin‐converting enzyme (ACE) inhibition improved cardiac fatty acid metabolism in patients with congestive heart failure (CHF). Myocardial 123I‐&bgr;‐methyl‐iodophenylpentadecanoic acid (123I‐BMIPP) imaging was performed in 25 patients with CHF and in 10 control subjects. Myocardial 123I‐BMIPP images were obtained 30 min and 4 h after tracer injection. The heart‐to‐mediastinum (H/M) ratio of 123I‐BMIPP uptake and the washout rate of 123I‐BMIPP from the myocardium were calculated. Patients were given enalapril for 6 months, and 123I‐BMIPP imaging was repeated. H/M ratios on early and delayed images were lower in CHF patients than in normal controls (P<0.01). The washout rate of 123I‐BMIPP from the myocardium was faster in CHF patients than in controls (P<0.01). As the severity of the New York Heart Association (NYHA) functional class increased, the H/M ratio decreased and the washout rate increased. The washout rate of 123I‐BMIPP was inversely correlated with left ventricular fractional shortening (R = ‐0.62, P < 0.01). ACE inhibition with enalapril increased the H/M ratio on delayed images (P<0.05) and reduced the washout rate of 123I‐BMIPP (P<0.05) in CHF patients. These data suggest that: (1) angiotensin II‐mediated intracellular signalling activation may be a possible mechanism for the decreased myocardial uptake and enhanced washout of 123I‐BMIPP in heart failure patients; and (2) the improvement in fatty acid metabolism by ACE inhibition may represent a new mechanism for the beneficial effect of this therapy in heart failure. (© 2003 Lippincott Williams & Wilkins)

Dynamic123I-MIBG SPECT reflects sympathetic nervous integrity and predicts clinical outcome in patients with chronic heart failure

Abstract123I-metaiodobenzylguanidine (123I-MIBG) is useful for assessment of the severity and prognosis of patients with chronic heart failure (CHF). To examine123I-MIBG kinetics in the early phase soon after tracer injection, we performed dynamic single photon emission computed tomography (SPECT) in 76 patients with CHF and 17 control subjects. The consecutive 15 images of 2 min-dynamic SPECT were acquired for 30 min after injection. From 0 to 4 min, a significant amount of radioactivity existed in the blood pool, thus we calculated washout rate of123I-MIBG from 4 to 30 min (%WR-E). Patients were followed up with an end-point of cardiac death or re-hospitalization for 16 months (6–30 months). As the NYHA functional class advanced, %WR-E increased (control, NYHA class I, II, and III: 9 ± 4%, 10 ± 5%, 12 ± 5%, and 17 ± 5%*, respectively, *p < 0.01 vs. all other groups). Significant correlation was found between %WR-E and conventional WR from 30 min to 240 min (r = 0.606, p < 0.0001). %WR-E was positively correlated with left ventricular end-diastolic dimension (r = 0.372, p < 0.01 ) and was inversely correlated with left ventricular fractional shortening (r = -0.316, p < 0.02). The normal upper limit of %WR-E was defined as mean + 2SD value of 17 control subjects (17.1%). Patients with abnormally rapid %WR-E levels had a higher cardiac event rate than those with normal %WR-E levels (57% vs. 12%, p < 0.0001). These data suggest that washout rate of123I-MIBG in the early phase from 4 min to 30 min (%WR-E) reflects cardiac sympathetic nervous integrity and is useful to evaluate the severity and prognosis of patients with CHF. The present results indicate a potential role of dynamic SPECT in shortening the123I-MIBG imaging protocol.

Electrophysiologic Effects of Sodium Channel Blockade on Anisotropic Conduction and Conduction Block in Canine Myocardium: Preferential Slowing of Longitudinal Conduction by Flecainide Versus Disopyramide or Lidocaine

OBJECTIVES The purpose of this study was to determine the effects of sodium channel blockade on anisotropic excitation propagation in the intact canine left ventricle. BACKGROUND Anisotropic ventricular conduction- electric conductivity dependent on the myocardial fiber direction-is one of the important mechanisms of ventricular arrhythmia. However, the effects of sodium channel blockade, especially the differential effect of a subclass of this agent, on the anisotropic properties remain unknown. METHODS In 28 anesthetized, open chest dogs, a small cannula was inserted into the left anterior descending coronary artery. Saline (control), disopyramide, lidocaine or flecainide was infused selectively into the cannula. An array of 64 epicardial electrodes was placed on the anterior surface of the ventricle. Activation time (AT) was measured along the longitudinal (L) and transverse (T) directions. RESULTS High dose flecainide (100 microg/kg body weight per min) delayed the AT along the L direction markedly (mean [+/-SE] 227 +/- 38%, p < 0.02) and mildly (121 +/- 10%, p < 0.02) along the T direction in regular beats (p < 0.007, L vs. T). Lidocaine and disopyramide did not show direction-dependent prolongation of the AT on regular beats. When examined on premature beats, AT was delayed, depending on the coupling interval and the fiber direction when saline, flecainide or lidocaine was infused. The conduction blocks along the L direction were observed in three of seven dogs on regular beats after flecainide and ventricular fibrillation ensued in two of these three dogs. CONCLUSIONS A peculiar slowing of L conduction by flecainide may relate to the character of proarrhythmia.

Enhanced regional washout of technetium-99m-sestamibi in patients with coronary spastic angina.

Background: Reverse redistribution and rapid washout of99mTc-sestamibi are observed in patients with acute myocardial infarction and may indicate viable myocardium. However, the clinical significance of this phenomenon has not been rigorously examined in other cardiac diseases. Thus, we investigated whether reverse redistribution and washout of99mTc-sestamibi could be used in the diagnosis and follow-up of patients with coronary spastic angina.Methods: Thirty patients diagnosed as coronary spastic angina were examined. During coronary arteriography, spasm was induced by provocation test with ergonovine, and only total or subtotal occlusion was considered positive. Myocardial perfusion tomography was obtained 45 min (early) and 3 hr (delayed) after99mTc-sestamibi injection. Segmental defect score was visually graded from 0 (normal) to 4 (defect), and a total defect score was determined as the sum of defect scores for all segments. Washout rate of99mTc-sestamibi from the myocardium was calculated for all segments. Washout rate of99mTc-sestamibi from the myocardium was calculated for each segment. After medical treatment with calcium antagonists and nitrates for 3 months,99mTc-sestamibi imaging was repeated.Results: Out of 30 patients, on the early images 17 (57%) patients demonstrated decreased99mTc-sestamibi uptake in spastic segments; on the other hand, 24 (80%) patients did decreased99mTc-sestamibi uptake in spastic segments on delayed images. Total defect scores in delayed images were higher than those in early images (6.9±0.3 vs. 3.6±0.4, p<0.01). Reverse redistribution of99mTc-sestamibi was observed in 17 out of 30 patients (57%) with coronary spastic angina. Washout rate of99mTc-sestamibi from spastic segments was higher than that from nonspastic segments (16±2% vs. 11±5%, p<0.01). After medical treatment, washout rate from spastic segments was decreased to 10±4 (p<0.01), and left ventricular ejection fraction was increased from 63±8% to 73±4% (p<0.01).Conclusion: Rapid washout of99mTc-sestamibi was observed in patients with coronary spastic angina and might indicate that the ability of myocyte to retain the tracer was impaired due to repetitive brief ischemia by coronary spasm. The early and delayed99mTc-sestamibi imaging provides useful information for the diagnosis and responses to the treatment in patients with coronary spastic angina.

Relation between activation sequence fluctuation and arrhythmogenicity in sodium-channel blockades

To examine the correlation between activation sequence fluctuation and arrhythmogenicity, we investigated temporal changes in the activation sequence by measuring activation times [negative first derivative of voltage over time (-dV/dt) in QRS] from the entire heart in 18 dogs. The heart was paced by constant atrial stimulation. The character of the activation sequence fluctuation was established by a principal component analysis, in which the first principal component was defined as a stable component of the sequence and the second or third component as a fluctuated component. Steady state contained 2.2 +/- 0.6% (percent total principal component, mean +/- SD) of fluctuated components, which appeared in a beat-by-beat manner (activation sequence alternans). Activation sequence alternans was observed only during flecainide administration and not during lidocaine or disopyramide administration. Fluctuated components at a high dose of flecainide significantly increased (3.3 +/- 0.8%). Ventricular fibrillation ensued in all dogs (n = 6) exposed to flecainide after an increase in activation sequence alternans. In conclusion, flecainide evoked local activation sequence alternans. This phenomenon correlated with the occurrence of ventricular fibrillation.

Effects of activation sequence on monophasic action potential configuration in the dog

The effects of altered activation sequence on the monophasic action potential (MAP) in in situ beating hearts are not known, although its effects on refractory periods are well documented. In nine anesthetized, open-chest dogs, complete atrioventricular block was produced, and the heart was driven by either right ventricular or left ventricular stimulation. The MAPs of the right and left ventricles were recorded by contact electrodes at cycle lengths of 1,000, 800, 600, and 400 ms. The MAP configuration was evaluated with regard to the difference between phase 1 and phase 2 MAP amplitudes and MAP duration at 50 and 90% repolarization. An MAP recorded from the ventricle that was being electrically stimulated was designated an ipsilateral ventricular stimulation, whereas the MAP recorded from the nonstimulated ventricle was termed a contralateral ventricular stimulation. The difference in amplitude and the 50% and 90% MAP durations for ipsilateral ventricular stimulation were consistently larger than for contralateral ventricular stimulation at all cycle lengths tested. Transient outward current did not appear to play a major role in producing such differences in MAP because intravenous treatment with 4-aminopyridine, a blocker of transient outward current, did not affect the configuration of the MAP. These findings provide an insight on the influence of ventricular activation sequence on the shape of the transmembrane action potential.